The tissue engineering (“TE”) approach generally includes the delivery of a biocompatible tissue substrate that serves as a scaffold or support onto which cells may attach, grow and/or proliferate, thereby synthesizing new tissue by regeneration or new tissue growth to repair a wound or defect. Open cell biocompatible foams have been recognized to have significant potential for use in the repair and regeneration of tissue. However, because of their ability to break down and be absorbed by the body without causing any adverse tissue response during and after the body has synthesized new tissue to repair the wound, prior work in this area has focused on tissue engineering scaffolds made from synthetic bioabsorbable materials.
Several attempts have been made to make bioabsorbable TE scaffolds using various processing methods and materials such as those described in U.S. Pat. No. 5,522,895 (Mikos), U.S. Pat. No. 5,514,378 (Mikos et al.), U.S. Pat. No. 5,133,755 (Brekke), U.S. Pat. No. 5,716,413 (Walter et al.), U.S. Pat. No. 5,607,474 (Athanasiou et al.), U.S. Pat. No. 6,306,424 (Vyakarnam et. al), U.S. Pat. No. 6,355,699 (Vyakarnam et. al), U.S. Pat. No. 5,677,355 (Shalaby et al.), U.S. Pat. No. 5,770,193 (Vacanti et al.), and U.S. Pat. No. 5,769,899 (Schwartz et al.). Synthetic bioabsorbable biocompatible polymers used in the above-mentioned references are well known in the art and, in most cases, include aliphatic polyesters, homopolymers and copolymers (random, block, segmented and graft) of monomers such as glycolic acid, glycolide, lactic acid, lactide (d, 1, meso or a mixture thereof), ε-caprolactone, trimethylene carbonate and p-dioxanone.
The major weaknesses of these approaches relating to bioabsorbable three-dimensional porous scaffolds used for tissue regeneration are undesirable tissue response during the product's life cycle as the polymers biodegrade and the inability to engineer the degradation characteristics of the TE scaffold in vivo, thus severely limiting their ability to serve as effective scaffolds. Also, there remains a need for an implant that withstands compression in a delivery-device during delivery to a biological site, e.g., by a catheter, endoscope, arthoscope or syringe, capable of expansion by resiliently recovering to occupy and remain in the biological site, and of a particular pore size such that the implant can become ingrown with tissue at that site to serve a useful therapeutic purpose. Furthermore, many materials produced from polyurethane foams formed by blowing during the polymerization process are unattractive from the point of view of biodurability because undesirable materials that can produce adverse biological reactions are generated during polymerization, for example, carcinogens, cytotoxins and the like. In contrast, the biodurable reticulated elastomeric matrix materials of the present invention are suitable for such applications as long-term TE implants, especially where dynamic loadings and/or extensions are experienced, such as in soft tissue related orthopedic applications.
A number of polymers having varying degrees of biodurability are known, but commercially available materials either lack the mechanical properties needed to provide an implantable device that can be compressed for delivery-device delivery and can resiliently expand in situ, at the intended biological site, or lack sufficient porosity to induce adequate cellular ingrowth and proliferation. Some proposals of the art are further described below.
Brady et al., in U.S. Pat. No. 6,177,522 (“Brady '522”), disclose implantable porous polycarbonate polyurethane products comprising a polycarbonate that is disclosed to be a random copolymer of alkyl carbonates. Brady '522's crosslinked polymer comprises urea and biuret groups, when urea is present, and urethane and allophanate groups, when urethane is present.
Brady et al., in U.S. Patent Application Publication No. 2002/0072550 A1 (“Brady '550”), disclose implantable porous polyurethane products formed from a polyether or a polycarbonate linear long chain diol. Brady '550 does not broadly disclose a biostable porous polyether or polycarbonate polyurethane implant having a void content in excess of 85%. The diol of Brady '550 is disclosed to be free of tertiary carbon linkages. Additionally, Brady '550's diisocyanate is disclosed to be 4,4′-diphenylmethane diisocyanate containing less than 3% 2,4′-diphenylmethane diisocyanate. Furthermore, the final foamed polyurethane product of Brady '550 contains isocyanurate linkages and is not reticulated.
Brady et al., in U.S. Patent Application Publication No. 2002/0142413 A1 (“Brady '413”), disclose a tissue engineering scaffold for cell, tissue or organ growth or reconstruction, comprising a solvent-extracted, or purified, reticulated polyurethane, e.g. a polyether or a polycarbonate, having a high void content and surface area. Certain embodiments employ a blowing agent during polymerization for void creation. A minimal amount of cell window opening is effected by a hand press or by crushing and solvent extraction is used to remove the resulting residue. Accordingly, Brady '413 does not disclose a resiliently-compressible reticulated product or a process to make it.
Gilson et al., in U.S. Pat. No. 6,245,090 B1 (“Gilson”), disclose an open cell foam transcatheter occluding implant with a porous outer surface said to have good hysteresis properties, i.e., which, when used in a vessel that is continually expanding and contracting, is said to be capable of expanding and contracting faster than the vessel. Gilson's open cell foam is not reticulated.
Pinchuk, in U.S. Pat. Nos. 5,133,742 and 5,229,431 (“Pinchuk '742” and “Pinchuk '431”, respectively), discloses a crack-resistant polyurethane said to be useful for medical prostheses, implants, roofing insulators and the like. The polymer is a polycarbonate polyurethane polymer which is substantially completely devoid of ether linkages.
Szycher et al., in U.S. Pat. No. 5,863,627 (“Szycher”), disclose a biocompatible polycarbonate polyurethane with internal polysiloxane segments.
MacGregor, in U.S. Pat. No. 4,459,252, discloses cardiovascular prosthetic devices or implants comprising a porous surface and a network of interconnected interstitial pores below the surface in fluid flow communication with the surface pores.
Gunatillake et al., in U.S. Pat. No. 6,420,452 (“Gunatillake '452”), disclose a degradation resistant silicone-containing elastomeric polyurethane. Gunatillake et al., in U.S. Pat. No. 6,437,073 (“Gunatillake '073”), disclose a degradation-resistant silicone-containing polyurethane which is, furthermore, non-elastomeric.
Pinchuk, in U.S. Pat. No. 5,741,331 (“Pinchuk '331”), and its divisional U.S. Pat. Nos. 6,102,939 and 6,197,240, discloses supposed polycarbonate stability problems of microfiber cracking and breakage. Pinchuk '331 does not disclose a self-supporting, space-occupying porous element having three-dimensional resilient compressibility that can be catheter-, endoscope-, or syringe-introduced, occupy a biological site and permit cellular ingrowth and proliferation into the occupied volume.
Pinchuk et al., in U.S. Patent Application Publication No. 2002/0107330 A1 (“Pinchuk '330”), disclose a composition for implantation delivery of a therapeutic agent which comprises: a biocompatible block copolymer having an elastomeric block, e.g., polyolefin, and a thermoplastic block, e.g., styrene, and a therapeutic agent loaded into the block copolymer. The Pinchuk '330 compositions lack adequate mechanical properties to provide a compressible catheter-, endoscope-, or syringe-introducible, resilient, space-occupying porous element that can occupy a biological site and permit cellular ingrowth and proliferation into the occupied volume.
Tuch, in U.S. Pat. No. 5,820,917, discloses a blood-contacting medical device coated with a layer of water-soluble heparin, overlaid by a porous polymeric coating through which the heparin can elute. The porous polymer coating is prepared by methods such as phase inversion precipitation onto a stent yielding a product with a pore size of about 0.5-10 μm. Tuch's disclosed pore sizes are too small for effective cellular ingrowth and proliferation of uncoated substrates.
The above references do not disclose, e.g., an implantable device that is entirely suitable for delivery-device delivery, resilient recovery from that delivery, and long-term residence as a tissue engineering scaffold with the therapeutic benefits, e.g., tissue repair and regeneration, associated with appropriately-sized interconnected pores. Moreover, the above references do not disclose, e.g., such a device containing polycarbonate moieties.
The foregoing description of background art may include insights, discoveries, understandings or disclosures, or associations together of disclosures, that were not known to the relevant art prior to the present invention but which were provided by the invention. Some such contributions of the invention may have been specifically pointed out herein, whereas other such contributions of the invention will be apparent from their context. Merely because a document may have been cited here, no admission is made that the field of the document, which may be quite different from that of the invention, is analogous to the field or fields of the invention. The citation of any reference in the background section of this application is not an admission that the reference is prior art to the application.